Diabetes mellitus is a common disorder associated with high morbidity and mortality. Though, it is more prevalent in developed countries, its incidence in developing countries is steadily increasing due to rapid changes in lifestyle. Type 2 diabetes affects up to 10% of all adults in the general population and up to 20% of people aged over 65, and is a major risk factor for cardiovascular, eye, kidney, and nerve disease. (National Institutes of Health, NIH Publication No. 95-1468, 1995, pp. 47-68.)
Several antidiabetic agents with different mechanisms of action are known for use in the treatment of diabetes Mellitus. Sulphonylureas and biguanides have been mainstay of therapy in diabetes mellitus. Though oral monotherapy is successful in initial stages of treatment, however, it is often associated with a high secondary failure rate on continued use, which contributes to the development of long term diabetes complications as a result of persistent hyperglycemia. (Am J. Med. 2000 Apr. 17; 108 Suppl 6a:15S-22S.)
In order to reduce and maintain blood glucose levels in normal ranges, evidences suggest that combination therapy using oral antidiabetic agents with different mechanisms of action may be effective. Such combination therapy offers not only enhanced glycaemic control, but also reduces adverse reactions and thus better outcomes in the management of diabetes.
One such combination known is that of sulphonylurea compounds plus metformin, which is somewhat effective in solving the underlying defects in the disorder, i.e., both insulin deficiency and insulin resistance. Sulphonylurea compounds commonly used in medicinal application includes Glimipiride, Glipizide, Gliclazide, and Glibenclamide.
Sulphonylurea derivatives act by binding to sulphonylurea receptors on pancreatic β-cells, leading to increased secretion of insulin. Possible mechanism of actions of metformin includes inhibition of hepatic gluconeogenesis by decreasing hepatic insulin resistance; delaying/inhibiting absorption of glucose from the gastrointestinal tract and increasing the insulin sensitivity and glucose uptake in the cells.
Often patients on combination therapy with sulphonylureas and metformin are not controlled and hence the option left is either addition of third drug or put patient on insulin therapy. Insulin therapy is not only costly but is not preferred due to poor patient compliance in parenteral application. New generation thiazolidinediones class of antidiabetic drugs, though useful in glycemic control, are associated with several adverse effects such as excessive risk of congestive heart failure, acute myocardial infarction, increased rate of bone loss and liver toxicity.
In the light of failure of monotherapy of antidiabetic drugs in glycemic control and increased adverse effects when administered at high doses of antidiabetic drugs for getting better glycemic control, newer medications for diabetes are needed, which will have good antihyperglycemic effect, as well as good tolerability profile.
Since Diabetes is also associated with risk of Coronary Heart disease (CHD) or increase in CHD incidence, a drug reducing blood glucose levels while giving cardiovascular benefits is preferable for the treatment of diabetes.
Hydroxychloroquine is a disease modifying antirheumatic drug (DMARD) and is being used in rheumatology for past four decades. The use of hydroxychloroquine is well established in rheumatoid arthritis and systemic lupus erythematosus.
Hydroxychloroquine is reported to show antidiabetic properties in many studies. However, the mechanism by which hydroxychloroquine improves glucose control remains unclear (Diabetes Res Clin Pract. 2002 March; 55(3):209-19).
The glucose lowering efficacy of hydroxychloroquine has been studied in various clinical trials. A study conducted in 135 obese patients with diabetes mellitus, showed that hydroxychloroquine improved glycemic control in sulphonylurea-refractory patients with poorly controlled Type 2 diabetes. (Diabetes Res Clin Pract. 2002 March; 55(3):209-19.) In another multicenter observational study of 4905 adults with rheumatoid arthritis indicated that use of hydroxychloroquine is associated with a reduced risk of diabetes. (JAMA. 2007 Jul. 11; 298(2):187-93). The reduction in blood glucose level is not very significant for making hydroxychloroquine as a monotherapy. It is being suggested as a prophylactic measure to prevent development of diabetes in patients with rheumatoid arthritis.
Hydroxychloroquine has shown efficacy in patients with resistant diabetes also. A study conducted in 38 patients with non insulin-dependent diabetes resistant to commonly used therapies (oral drugs, insulin, combination of insulin and oral drugs) showed statistically significant improvement in patients who received the insulin and Hydroxychloroquine which was compared with combination of glibenclamide with hydroxychloroquine. It was possible to reduce the daily insulin dose in patients treated with the combined insulin and hydroxychloroquine therapy by an average of 30%. The trial reveals that combining antidiabetic therapy with hydroxychloroquine in decompensated, treatment-refractory patients with noninsulin-dependent diabetes may help to break the vicious circle of hyperglycemia and lead to better management of the disease. (Ann Intern Med. 1990 May 1; 112(9):678-81)
Along with antihyperglycaemic effects, hydroxychloroquine is also associated with cardiovascular benefits, due to its lipid lowering effect and antiplatelet effect.
Improvement of serum cholesterol in patients treated with hydroxychloroquine has been reported. These include a decrease in serum levels of cholesterol by approximately 10% and an increase in low-density lipoprotein receptors. Hydroxychloroquine also led to a rise in both HDL and % HDL. (Ann Rheum Dis. 1997 June; 56(6):374-7.)
Hydroxychloroquine therapy had a high statistical association with low serum levels of cholesterol, triglycerides, and LDL, irrespective of concomitant steroid administration. The hydroxychloroquine-treated group had lower cholesterol and LDL levels than those receiving neither hydroxychloroquine nor steroids. Very-low-density lipoprotein cholesterol was reduced in the group receiving hydroxychloroquine, and this was associated with decreased plasma triglycerides in this group. (Br J Rheumatol. 1985 August; 24(3):250-5.)
In addition to its lipid lowering effect, hydroxychloroquine may be cardioprotective by reducing platelet aggregation.
Hydroxychloroquine causes reduction in red blood cell aggregation without prolonging the bleeding time in humans and experimentally, reduces the size of the thrombus. There is a variably demonstrable reduction in platelet aggregation and blood viscosity in humans. (Am J Med. 1988 Oct. 14; 85(4A):57-61)
A more recent clinical study found a significant reduction in plasma viscosity as well as whole blood viscosity in postoperative patients treated with hydroxychloroquine.
WO/2001/032758 discloses Pharmaceutical composition comprising a combination of metformin with other anti diabetic drug, wherein the other antidiabetic agent is one or more of glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, troglitazone, rosiglitazone, pioditazone, insulin and/or KRP-297.
In the light of failure of monotherapy of antidiabetic drugs in getting good glycemic control and increased adverse effects when administered at higher doses of antidiabetic drugs for getting better glycemic control, it is an object of the present invention to seek newer medication for the treatment of diabetes mellitus, a chronic disease. Surprisingly, combination of hydroxychloroquine with antidiabetic drugs such as sulphonylureas, biguanides and thiazolidinediones found to be an effective treatment for diabetes mellitus, meeting the object of the present invention.